A disease deflector

The outside world teems with microscopic objects. Many of these busy microbes invade the human body. Viruses, pollen, bacteria, fungi, toxins, mineral particles, soot, and—these days—microplastics permeate the food we eat and the air we breathe.

To combat this assault, the body uses a diverse tool kit: the immune system. The body’s response to threats depends upon its ability to generate an omnifarious defense, while the microbiome lining the gut surface contains a complexity that protects and sustains us in more ways than one. It’s tempting to conclude that diversity is always a faithful ally.

When a vertebrate immune system faces a new pathogen, it comes prepared with a variety of weapons. “The immune system is all about diversity,” said Akiko Iwasaki, PhD, the Waldemar Von Zedtwitz Professor of Immunobiology, professor of molecular, cellular, and developmental biology, and of dermatology, and a Howard Hughes Medical Institute investigator.

Each young cell of the adaptive immune response begins life wielding a unique appendage—a single type of receptor. Each receptor is generated afresh, one per cell, by genes that recombine and mutate rapidly.

If the pathogen happens to fit a single cell’s receptor—an event analogous to a random key fitting a lock—the lymphocyte that wields it begins to divide. Equipped with the correct receptor, all the cell’s progeny can more effectively meet the intruder.

Absent this process, there would be no adaptive immune response—a “clear example of diversity being required for survival,” Iwasaki said.

Similarly, at the population level, individual people muster a variable array of immune responses that limit the damage that any specific pathogen can do. People contract infectious diseases all the time, but few people are killed by them, save in examples in which people are immunocompromised or in cases where the pathogen is extremely deadly.

(Iwasaki has argued that the immunology community itself ought to follow similar principles in its own ranks, criticizing the ubiquity of homogeneous panels and speakers at research symposia.)

Then there is the gut microbiome. In recent years, studies about it have flourished, even as researchers have come to suspect that this inner ecosystem is growing less diverse due to restricted diets and antibiotic overprescribing over several decades. This loss of diversity is, it appears, to our detriment: a higher number of species in the gut microbiota seems to correlate with better health.

Severe loss of diversity in the gut microbiome can predispose a person to opportunistic infections. The classic example is Clostridium difficile infection (CDI), which can take hold after chronic antibiotic use eradicates ordinary gut residents. As it flourishes, CDI can cause a life-threatening diarrhea.

“[Antibiotic use can be] like clearing the rainforest in the gut,” said Noah Palm, PhD ’11, assistant professor of immunobiology. “This weed that was hiding in the background as spores is able to grow.”

Until recently, physicians treated repeat CDI episodes with antibiotics, a tactic comparable to burning over the same ground again and again. An alternative approach: replace the dangerously simple ecosystem with a diverse one using a fecal microbiota transplant. With cure rates topping 90%, it is now first-line therapy for third or subsequent nonsevere episodes of recurrent CDI. This success has inspired researchers to experiment with fecal microbiota transplantation in a wide variety of other diseases, including autoimmune disease, autism, and cancer.

Why did we evolve such a diverse gut community in the first place? One explanation is that it can shield us from colonization by pathogens, Palm said. Without friendly bacteria occupying all available ecological niches in the gut, a person is profoundly susceptible to infectious disease.

As an example, to infect a healthy mouse with Salmonella requires something like 100 million individual bacteria. But if you dose that mouse with an antibiotic, thus eradicating part of its gut flora, it may take only 100 or even 10 Salmonella cells to cause infection.

“In my opinion, that’s the most important rule that the microbiota plays evolutionarily,” Palm said. “Without our microbiota, for that reason alone, all of us would be dead from pathogenic infection.”

Over deep time, a certain level of gut microbiome diversity has become necessary for another reason: nutrition. We’ve lost the ability to synthesize certain vitamins on our own, instead depending on specific microbes to perform that metabolic task. The gut microbiome, too, can unlock complex carbohydrates whose nutrients would otherwise be out of reach.

On a local level, though, greater diversity isn’t necessarily better. Compared with the gut, for instance, the vagina prefers a far simpler microbiome. Whether the lung does best with a wide or narrow range of organisms remains to be determined.

Andrew Goodman, PhD, the C.N.H. Long Professor of Microbial Pathogenesis, and director of the Yale Microbial Sciences Institute, emphasizes the importance of avoiding the reflexive belief that diversity is invariably beneficial to biological systems.

In clinical care, for example, fecal transplantation has not fulfilled everyone’s hopes.

“To date, [CDI is] really the only example where there’s been widespread clinical application of a microbiome-based therapy that’s gone beyond a few isolated trials,” Goodman said.

Even in the gut, the addition of a new kind of microbe—ratcheting up the diversity, he points out—is arguably less healthful if the newcomer is a pathogen.

Palm added that many recent non-CDI fecal transplantation trials have little basis beyond hope on which to proceed.

“People are throwing darts at a wall without understanding what’s going on” he said. “It’s much less clear that loss of diversity is actually a cause of disease in these other, more chronic disorders.”

“The idea of diversity being good, I think, has caught hold because it’s an attractive idea, and fits with our concepts also of biodiversity environmentally,” Palm added. “It’ll be interesting … to figure out in a bit more mechanistic detail when and why it’s actually good to have diversity, and get beyond some of these generalizations.”

If fecal transplantation turns out not to be a panacea, what other roles might gut biodiversity play in clinical care? Goodman, for his part, is studying the role played by the gut microbiome in the body’s response to medications. People with the same disease can have different responses to the same drug. Some of that variability may be explained by differences in the human genome, but the gut microbiome’s genome, which dwarfs that of its human host, may also be involved.

Goodman points out that researchers have identified gut microbes that metabolize two-thirds of the medications they’ve examined. How those metabolites affect the host is still unknown, he said, “but at least the potential is there. We’re just starting to understand the rules.”

“I’ve always been interested in the molecular mechanisms of gut microbial ecology. We have a lot more to learn,” Goodman said. “It’s a very fun time and a very exciting time to be in the field.”